Why Do Antidepressants Take So Long to Work?

Kate wanted to die. She remembers the moment the psychiatrist said “the antidepressant isn’t going to work right away. Can you promise to be here next week and not kill yourself?” “I told her no,” Kate says.

Kate wanted to die. She remembers the moment the psychiatrist said “the antidepressant isn’t going to work right away. Can you promise to be here next week and not kill yourself?”

“I told her no,” Kate says. “I couldn't promise my doctor I’d make it a week. That’s how bad my life had to be before I got help. When you’re struggling to stay alive every single day, and then your doctor tells you it’s going to take two to six weeks before the medications they give you are going to work, it’s devastating.” To make matters worse, after those weeks, the drug didn’t work. Kate went through five different anti-depressants over the course of six months before confirming that none of them worked. The debilitating disorder kept her out of school for extended periods of time.

The National Center for Health Statistics estimates more than one in 10 Americans over the age of 12 took antidepressants between 2005 and 2008, the last time period for which the data are available. The rate of antidepressant use increased 400 percent from 1998 to 2008.

Traditional antidepressants go after serotonin transporter proteins. These regulatory proteins take serotonin back into the nerve cell after it has been released in the process of signaling other neurons. Antidepressants keep the transporters from performing this function.

Although nowadays, most scientists feel that serotonin release and reuptake are fairly normal in depressed patients, many scientists nonetheless believe the changes in serotonin signaling caused by antidepressants, induces the alleviation of symptoms, says Gary Rudnick, professor of pharmacology at Yale School of Medicine.

Still, antidepressants stop the process of serotonin transporters sucking up released serotonin fairly quickly, so researchers don’t understand why it takes weeks for the medications to take effect, Rudnick says. Scientists believe the behavioral effects of antidepressants may be due to other changes that occur as a reaction to the changed serotonin levels. However, researchers don’t know what reactions include, and therefore cannot create medications that target them directly.

Targeting proteins

A large portion of depression research is associated with trying to ascertain the role of neurogenesis, the process by which the brain generates new neurons. Researchers have noticed that the hippocampus of a depressed person’s brain tends to be smaller than average. Some researchers hypothesize that a problem with neurogenesis causes both the small hippocampus as well as depression; others caution that the causal arrow may be reversed, with a small hippocampus leading to problems with neurogenesis and depression.

“Chronic [or long term] antidepressant treatment will actually increase levels of neurogenesis,” says Julie Blendy, a neuroscientist and pharmacologist at the Perelman School of Medicine at the University of Pennsylvania. Chronic treatment will also increase levels of the protein CREB, known to play a role in the long-term effects of anti-depressants.

To test the effectiveness of CREB, Blendy got rid of the protein in mice. Of course, CREB doesn’t work in a vacuum, and another protein CREM upregulated (increased) in order to compensate for the missing CREB. Interested in the effects of CREM, Blendy upregulated CREM without touching CREB, and found the antidepressants acted much quicker. This new development, published in The Journal of Neuroscience in August 2013, suggests that identifying CREM targets would be better than attempting to identify CREB targets.

Ketamine

An increasingly popular antidepressant solution involves Ketamine, more popularly known as the illicit drug ‘Special K.’ Ketamine has been shown to be effective in bipolar and depressed patients who have not responded to other antidepressants. The drug works in just two hours.

The use of ketamine as an antidepressant has been called the first true development in the field of antidepressant research in 50 years, for it targets an entirely different part of the brain than traditional antidepressants. Instead of focusing on serotonin, norepinephrine or dopamine neurotransmitters, ketamine focuses on a glutamate neurotransmitter. Glutamate accounts for more than 90 percent of all synapses in the human brain, which makes it the most prevalent of all neurotransmitters.

Further studies need to be done in order to figure out how patients can use the drug without experiencing dangerous side effects, such as severe inflammation of the bladder and addiction. Abundant research also needs to be done to further Blendy’s work. Although she and her team of researchers have shown that CREM is a promising target for antidepressants, targeting that protein with a new drug will be a whole new challenge.

Editor’s note (11/15/13): This blog was edited after its original posting to correct an erroneous description of the effects of antidepressants on serotonin levels in the brain.

About the Author: Julianne Chiaet writes about science and technology. Follow her on Twitter @JuliChiaet

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